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Rinnakkaistallenteet Terveystieteiden tiedekunta
2019
Incidence of head injury and traumatic brain injury among people with
Alzheimer's disease
Ilmaniemi, S
BMJ
Tieteelliset aikakauslehtiartikkelit
© Authors
CC BY-NC http://creativecommons.org/licenses/by-nc/4.0/
http://dx.doi.org/10.1136/jech-2018-211960
https://erepo.uef.fi/handle/123456789/7496
Downloaded from University of Eastern Finland's eRepository
TITLE
Incidence of head injury and traumatic brain injury among people with Alzheimer's Disease
AUTHORS
Sarianna Ilmaniemi1, Heidi Taipale1,2,3,4, Antti Tanskanen3,4,5, Jari Tiihonen3,4,5, Sirpa Hartikainen1,2, Anna-Maija Tolppanen1,6
Affiliations:
1School of Pharmacy, University of Eastern Finland, Kuopio, Finland
2Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland 3Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden
4University of Eastern Finland, Department of Forensic Psychiatry, Niuvanniemi Hospital, Kuopio, Finland
5National Institute for Health and Welfare, Helsinki, Finland
6Research Centre for Comparative Effectiveness and Patient Safety (RECEPS), University of Eastern Finland, Kuopio, Finland
*Corresponding author. Sarianna Ilmaniemi, School of Pharmacy, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland. E-mail: sariilm@uef.fi
ABSTRACT
Background: Injuries caused by falling are a major health concern among older population. For older people, falls are the leading cause of head injuries, especially persons with cognitive disorders have an increased risk of falling.
Objective: To compare the incidence of head injury and traumatic brain injury (TBI) among persons with Alzheimer’s disease (AD) to persons without AD.
Methods: This register-based study was conducted a nationwide cohort, which includes all community-dwelling persons diagnosed with AD in Finland in 2005-2011. Persons with previous head injuries were excluded leaving 67,172 persons with AD. For each person with AD, a matching person without AD and previous head injury were identified with respect to age, sex and university hospital district. The Cox proportional hazard model and competing risk analyses were used to estimate hazards ratios for head injury and TBI.
Results: Persons with AD had 1.34-fold (95% CI 1.29 - 1.40) risk of head injuries and 1.49-fold (95% CI 1.40 - 1.59) risk of TBIs after accounting for competing risks of death and full adjustment by socioeconomic status, drug use and comorbidities.
Conclusion: Persons with AD are more likely to have a head injury or TBI incident than persons without AD.
INTRODUCTION
Injuries caused by falling are a major health concern among older people and fall prevention is one of the key priorities in World Health Organization strategy to support healthy aging in Europe.[1]
Persons with Alzheimer’s disease (AD) or other forms of dementia have an increased risk of falling.[2,3] The majority of injury-related hospitalisations among persons with dementia are due to falls, and incidence of many injury types is higher compared to persons without dementia.[4]
Persons with cognitive impairment are more likely to fall and to experience a head or traumatic brain injury (TBI) than those without cognitive disorder.[4–7] However, these studies have included persons with all types of dementive disorders and have not separately assessed the risk among persons with AD. The aim of this study is to compare the incidence of head injuries and TBIs among persons with and without AD in a nationwide cohort.
DATA AND METHODS Study cohort
This register-based study was conducted in the Medication use and Alzheimer’s disease (MEDALZ) cohort, which includes all community-dwelling persons who received a clinically verified AD diagnosis in Finland in 2005-2011.[8] More detailed descriptions of the MEDALZ cohort, the data collection and different registers are available in Tolppanen et al.[8] AD diagnoses were based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association’s (NINCDS-ADRDA) and Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for AD and identified from the special reimbursement register maintained by the Social Insurance Institution of Finland (SII). Briefly, the specific criterion is 1) symptoms consistent with mild or moderate AD, 2) a decrease in social capacity over a period of at least 3 months, 3) a computer tomography/magnetic resonance imaging scan, 4) exclusion of possible alternative diagnoses, and 5) confirmation of the diagnosis by a registered neurologist or geriatrician. Additionally, a physician must evaluate whether the patient has symptoms of other cognitive disorders such as vascular lesions or symptoms of Lewy body dementia and patients with these disorders are granted reimbursement if symptoms are considered to be mainly caused by AD. Summary of anamnestic information from the patients and family, as well as findings from clinical examination and all diagnostic findings are submitted to the SII, where experts in this field systematically evaluates the diagnostic evidence of each AD case and confirms whether the pre- specified criteria are met and special reimbursement for AD can be granted.
To assess the incidence of head injuries, persons with previous head injuries before AD diagnosis were excluded, leaving 67,172 persons with AD. For comparison purposes, a matching person without AD and previous head injury were identified from the SII database with respect to age, sex and university hospital district (overall N=134,344). The non-AD cohort may include persons with other cognitive disorder than AD. The follow-up for a person with AD and his/her comparison person started on the date of AD diagnosis (corresponding index date for comparison person), and ended on the date of head injury/ TBI, death or the end data linkage (31 Dec. 2015).
The MEDALZ data are collected from different national registers and all data were pseudonymised by the register maintainers so that personal identification numbers were replaced by research ids.
Therefore, according to Finnish law and Personal Data Act, informed consent or ethics committee approval are not needed because data used are routinely collected, anonymized and this research does not have effect on the treatment of study subjects.
Outcomes
Information on head injuries (ICD-10 codes S0.00-S09.9) and TBI (S06.0-S06.9) was obtained from the hospital discharge register maintained by the National Institute of Health and Welfare and the causes of death register maintained by Statistics Finland.
Confounders
Data on cardiovascular diseases (hypertension, coronary artery disease, familial hypercholesterolemia, heart failure, and cardiac arrhythmias; reimbursement codes 201, 205, 206, 207, 213), asthma/chronic obstructive pulmonary disease (COPD) (203, 210) and diabetes (103) were collected from the special reimbursement register. Data on strokes (ICD-10 codes I60-64), hip fractures (S72.0-S72.2) and substance abuse (F10–F19) were obtained from the hospital discharge register. Comorbidities diagnosed before the follow-up were included. Fall-Risk-Increasing Drugs (FRIDs) were chosen on the basis of on the recent systemic reviews [9–11] and identified by the Anatomical Therapeutic Chemical (ATC) codes C03C (loop/high-ceiling diuretics) N02A (opioids), N03A (antiepileptics), N05A (antipsychotics), N06A (antidepressants) and N05BA, N05CD and N05CF (benzodiazepines and related drugs). The medication use was defined by the purchase history within a year before the follow-up and data on the medication use were collected from the prescription register. The medication use was defined by the purchase history within a year before the follow-up.
The socioeconomic position was indicated as each person’s highest occupational social class from
1970 until three years before the follow-up began. Data on the occupational class were collected from the censuses of Statistics Finland.
Statistical Analysis
All statistical analyses were performed with Stata SE 14.2. Pearson's χ2 test was used for categorical data to compare differences in the baseline characteristics of persons with and without AD. In order to assess if persons with AD will more likely to have a head injury or TBI incident, the Cox proportional hazard model was used to estimate hazards ratios (HRs) for head injury and TBI.
Competing risk analyses were performed according to the Fine and Gray approach[12]. For head injuries, competing events were deaths without a head injury. For TBI, competing events were deaths without TBI and head injuries without TBI.
RESULTS
At baseline, the mean age of study participants was 79.97 years in the AD cohort and 79.93 in the non-AD cohort. Majority of participants were women (65.4%). The prevalence of all comorbidities (excluding asthma/COPD) and the use of psychotropics and opioids were higher among persons with AD (Table 1). For head injuries, the follow-up times for persons with and without AD were 314,361 and 367,542 person-years, respectively. For TBIs, the follow-up times were 314,491 and 367,613 person-years, respectively. During the follow-up, the incidence rate of head injury was 20.0 per 1000 person-years (n=6298, 9.38%) among persons with AD and 12.2 (n=4478, 6.67%) among comparison persons. The TBI incidence rate was 8.66 per 1000 person-years (n=2725, 4.06%) among persons with AD and 4.67 (n=1715, 2.55%) among persons without AD. During the follow-up 37,845 (56.3%) persons in the AD cohort and 23,100 (34.4%) persons in the non-AD cohort were censored due to death.
Persons with AD had 1.34 (95% CI 1.29 - 1.40) times higher risk of head injuries and 1.49 (95% CI 1.40 - 1.59) times higher risk of TBIs than comparison persons after accounting for competing risks and full adjustment by socioeconomic status, drug use and comorbidities (Table 2). The results were similar with the standard Cox model.
Table 1 Characteristics of persons with and without Alzheimer’s disease Characteristics
AD cohort n=67,172
n (%)
Non-AD cohort n=67,172
n (%) P
Age at baseline, mean
(95% CI) 79.97 (79.92-80.02) 79.93 (79.87-79.98)
matched
Sex matched
Women 43941 (65.4) 43941 (65.4) Men 23231 (34.6) 23231 (34.6)
Highest occupational class <0.001
Manager 14020 (20.9) 14345 (21.4) Office worker 5717 (8.51) 5626 (8.38) Farming/foresty 12707 (18.9) 13123 (19.5) Sales/industry/cleaning 28602 (42.6) 26241 (39.1)
Unknonw 5608 (8.35) 5527 (8.23)
Did not respond 518 (0.77) 2310 (3.44)
Any head injury 6298 (9.38) 4478 (6.67) <0.001
Any traumatic brain injury 2725 (4.06) 1715 (2.55) <0.001
Comorbidities
Any substance abuse 2029 (3.02) 1314 (1.96) <0.001 Hip fracture 3444 (5.13) 2179 (3.24) <0.001
Asthma or COPD 5826 (8.67) 6089 (9.06) 0.012
Diabetes 8931 (13.3) 7706 (11.5) <0.001 Cardiovascular disease 33923 (50.5) 33021 (49.2) <0.001
Stroke 6255 (9.31) 5359 (7.98) <0.001
Medication use
Antiepileptics 3739 (5.57) 3039 (4.52) <0.001 Antipsychotics 7208 (10.7) 2378 (3.54) <0.001 Antidepressants 15804 (23.5) 7201 (10.7) <0.001 BZRDs 33417 (49.7) 25952 (38.6) <0.001 Opioids 5675 (8.45) 6141 (9.14) <0.001 Loop-diuretics 12496 (18.6) 11788 (17.5) <0.001 One psychotropic druga 25380 (37.8) 21485 (32.0) <0.001 Two psychotropic drugs 12007 (17.9) 5856 (8.72) <0.001 Three psychotropic drugs 2345 (3.49) 778 (1.16) <0.001 COPD: chronic obstructive pulmonary disease, BZDR: benzodiazepine and related drugs
a Antipsychotic, antidepressant or BZRD
Table 2 Association of Alzheimer's disease with incidence of head and traumatic brain injuries (TBIs).
1 2
Cox model HR (95% CI) Competing risk model HR (95% CI) Outcome No. of
events Events per
1000 PY Model 1a Model 2b Model 3c Model 1a Model 2b Model 3c
HT
No AD 4478 12.2 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) AD 6298 20.0 1.63 (1.57 - 1.69) 1.51 (1.45 - 1.57) 1.51 (1.45 - 1.57) 1.42 (1.36 - 1.47) 1.34 (1.29 - 1.40) 1.34 (1.29 -
1.40)
TBI
No AD 1715 4.67 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) AD 2725 8.66 1.74 (1.64 - 1.85) 1.61 (1.52 - 1.72) 1.60 (1.51 - 1.71) 1.59 (1.50 - 1.69) 1.50 (1.41 - 1.59) 1.49 (1.40 -
1.59) 3 a Unadjusted
4 b Adjusted for occupational socioeconomic position and the use of antiepileptics, antipsychotics, antidepressants, loop-diuretics, opioids and 5 benzodiazepines and related drugs within a year before the follow-up
6 c Adjusted for covariates in Model 2 and cardiovascular diseases, hip fractures, strokes, asthma or COPD, diabetes and substance abuse 7
DISCUSSION
Cognitive impairment and dementia are established risk factors for head injury or TBI.[4–7] To our knowledge, this the first study to show that persons with AD are at significantly higher risk for head injuries and TBIs compared to other older adults, also after accounting for higher risk of death in persons with AD.
For older adults, falls are the leading cause of head injury and TBI.[14,15] AD affects balance, gait[16] and visual capabilities[17] which may increase the risk of falling. Among persons with cognitive impairment, behavioural symptoms have also been associated with falls.[18] The high prevalence of psychotropic drug use may also partly impact on the higher incidence of head injury and TBI as these drugs increase the risk of falling.[10] However in our study, the analyses were adjusted for use of psychotropic drugs and other FRIDs.
Consequences of head or brain injuries are particularly serious for persons with AD. Previous studies found, that people with dementia have higher one-month and one-year mortality rates after head injury or TBI than those without cognitive disorder[4,7], and the functional outcome after TBI is often worse for older adults than for younger persons.[14,19] In addition, persons with dementia have longer hospital stays after TBI, but they are less likely to receive in-hospital rehabilitation.[7]
Strengths of this study include a large representative nationwide cohort that includes community- dwelling persons with AD diagnosis in Finland from 2005 to 2011. All AD cases were identified from the special reimbursement register and it has been shown to have a high positive predictive value and reasonably good sensitivity for AD.[20]
Our register-based study has some limitations. The data does not include information on lifestyle factors such as smoking and alcohol use or information on physical and social activity, but comorbidities and medications captures these factors to some extent. Head injuries and TBI were identified from the hospital discharge and causes of death registers and thus, our data includes only the most severe injuries and may underestimate the true incidence of head injuries and TBIs.
Our study compares the risk of head injuries only between persons with and without AD, not between persons with and without any cognitive disorder as persons with other forms of dementia were not excluded from the comparison cohort. However, AD is the most common disease leading to dementia and our results are representative of the association between dementia and head injuries, although the inclusion of persons with other forms of dementia in the comparison group dilutes the association.
Persons with AD are at higher risk for head and traumatic brain injuries than other older persons.
Therefore, prevention of falls and consequent injuries is essential as they cause suffering and can advance loss of activities of daily living, independence and the need of residential care.
ACKNOWLEDGEMENTS
MSc Billy Braithwaite is acknowledged for language editing of the manuscript.
AUTHOR CONTRIBUTIONS
SH and AMT planned the study. SI performed statistical analyses, drafted the first version of the manuscript and acts as a guarantor. AT and HT preprocessed and modelled prescription data. All authors contributed to the interpretation of the data, revised the manuscript, and approved the final manuscript.
FUNDING
AMT is funded by Academy of Finland (grants 307232 and 295334), HT and AMT acknowledge strategic funding from the University of Eastern Finland. The funders had no role in study design;
in the collection, analysis, and interpretation of data, in the writing of the report; and in the decision to submit the paper for publication.
COMPETING INTEREST
SI and AMT report no competing interests. SH reports lecture fees from MSD and Professio. HT and AT have participated in research projects funded by Janssen and Eli Lilly with grants paid to the institution where they were employed. AT is a member of advisory board of Janssen. JT has served as a consultant to the Finnish Medicines Agency Fimea, AstraZeneca, Bristol-Myers Squibb,
What is already known on this subject?
• Persons with cognitive disorders have a higher risk of falling and consequent injuries.
• Falls are the leading cause of head injuries among older adults.
• The risk of head injuries have not been assessed separately among person with Alzheimer's disease.
What this study adds?
• Our study shows that persons with Alzheimer's disease have a higher risk of head or traumatic brain injuries than persons without Alzheimer's disease
Eli Lilly, F. Hoffman-La Roche, Janssen-Cilag, Lundbeck, and Organon; he has received fees for giving expert testimonies to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Otsuka and Pfizer; lecture fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Novartis, Otsuka, Pfizer; and grants from Stanley Foundation and Sigrid Jusélius Foundation. Tiihonen is a member of the advisory boards for AstraZeneca, Eli Lilly, Janssen-Cilag, and Otsuka, and has participated in research projects funded by Janssen-Cilag and Eli Lilly with grants paid to Karolinska Institutet.
LICENCE FOR PUBLICATION
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence on a worldwide basis to the BMJ Publishing Group Ltd to permit this article to be published in JECH and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence
(http://group.bmj.com/products/journals/instructions-for-authors/licence-forms).
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